Gene and MicroRNA Perturbations of Cellular Response to Pemetrexed Implicate Biological Networks and Enable Imputation of Response in Lung Adenocarcinoma

Gamazon, Eric R.; Trendowski, Matthew; Wen, Yujia; Wing, Claudia; Delaney, Shannon M.; Huh, Won Jae; Wong, Shan S.; Cox, Nancy J.; Dolan, Eileen

doi:10.1038/s41598-017-19004-3

Cited by 14 publications

(9 citation statements)

References 62 publications

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“…MicroRNAs (miRNA or miR) is a class of small, non-encoding RNA molecules (7). miRNAs serve important roles in several biological and pathological processes by promoting mRNA degradation or inhibiting mRNA translation, to negatively regulate target gene expression (8).…”

Section: Introductionmentioning

confidence: 99%

Upregulated miRNA‑182‑5p expression in tumor tissue and peripheral blood samples from patients with non‑small cell lung cancer is associated with downregulated Caspase 2 expression

Yang¹,

Dou²,

Sui³

et al. 2019

Exp Ther Med

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Lung cancer has the highest morbidity and mortality rates among all malignant tumors worldwide. Previous studies demonstrated that microRNA (miR)-182-5p may serve different roles in different types of cancer, including renal cell carcinoma and liver cancer. However, the functional role of miR-182-5p in non-small cell lung cancer (NSCLC) remains unknown. In the current study, the expression level of miR-182-5p in tumor tissue and peripheral blood samples obtained from patients with NSCLC was examined. The biological function of miR-182-5p on NSCLC cell proliferation was also investigated. Tissue and adjacent normal tissue samples were collected from 33 patients with NSCLC. In addition, peripheral blood samples were obtained from patients with NSCLC and 26 healthy control patients. The NSCLC cell line H1299 was used for all functional assays. Reverse transcription-quantitative polymerase chain reaction was used to determine the miR-182-5p or Caspase 2 (CASP2) mRNA expression levels in NSCLC tissue and peripheral blood samples, as well as in the NSCLC cell line. Western blotting was used to examine the protein expression level of CASP2 in tissue samples and cells, and ELISA was performed to measure the protein level of CASP2 in peripheral blood samples. MTT assay was performed to examine NSCLC cell proliferation. Flow cytometry was used to detect apoptosis. Dual-luciferase reporter assay was used to examine whether miRN182-5p directly interacts with CASP2. The current study demonstrated that miR-182-5p expression was upregulated in NSCLC tissue and peripheral blood samples from patients with NSCLC, which suggests that miR-182-5p, may serve a functional role in NSCLC. In addition, inhibition of miR-182-5p expression suppressed cell proliferation and enhanced cell apoptosis in NSCLC cells. CASP2 expression was downregulated in NSCLC tissue and peripheral blood samples from patients with NSCLC. The current study demonstrated that miR-182-5p may regulate NSCLC cell proliferation and apoptosis by regulating CASP2 expression as miR-182-5p directly binds with the 3′-untranslated region of CASP2, thereby regulating CASP2 expression.

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Section: Introductionmentioning

confidence: 99%

Upregulated miRNA‑182‑5p expression in tumor tissue and peripheral blood samples from patients with non‑small cell lung cancer is associated with downregulated Caspase 2 expression

Yang¹,

Dou²,

Sui³

et al. 2019

Exp Ther Med

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“…They control gene expression by combining with the messenger RNAs (mRNAs) of target genes, causing mRNA degradation or translation suppression (6,7). Numerous studies have demonstrated that the aberrant and disordered expression of miRNAs is involved in many malignant tumors, including LCs (8–12).…”

Section: Introductionmentioning

confidence: 99%

Expression levels and co‑targets of miRNA‑126‑3p and miRNA‑126‑5p in lung adenocarcinoma tissues: Αn exploration with RT‑qPCR, microarray and bioinformatic analyses

Chen

et al. 2018

Oncol Rep

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Lung adenocarcinoma (LUAD) is the most common histological subtype of lung cancer. Previous studies have found that many microRNAs (miRNAs), including miRNA-126-3p, may play a critical role in the development of LUAD. However, no study of LUAD has researched the synergistic effects and co-targets of both miRNA-126-3p and miRNA-126-5p. The present study used real-time quantitative polymerase chain reaction (RT-qPCR) to explore the expression values of miRNA-126-3p and miRNA-126-5p in 101 LUAD and 101 normal lung tissues. Ten relevant microarray datasets were screened to further validate the expression levels of miRNA-126-3p and −5p in LUAD. Twelve prediction tools were employed to obtain potential targets of miRNA-126-3p and miRNA-126-5p. The results showed that both miRNA-126-3p and −5p were expressed significantly lower in LUAD. A significant positive correlation was also present between miRNA-126-3p and −5p expression in LUAD. In addition, lower expression of miRNA-126-3p and −5p was indicative of vascular invasion, lymph node metastasis (LNM), and a later tumor/node/metastasis (TNM) stage of LUAD. The authors obtained 167 targets of miRNA-126-3p and 212 targets of miRNA-126-5p; 44 targets were co-targets of both. Eight co-target genes (IGF2BP1, TRPM8, DUSP4, SOX11, PLOD2, LIN28A, LIN28B and SLC7A11) were initially identified as key genes in LUAD. The results of the present study indicated that the co-regulation of miRNA-126-3p and miRNA-126-5p plays a key role in the development of LUAD, which also suggests a fail-proof mode between miRNA-3p and miRNA-126-5p.

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“…MTHFD2 is regulated directly by several miRNAs in different cancer cells. For example, hsa‐miR‐202 has been predicted to target MTHFD2 in lung cancer with MTHFD2 showing enhanced expression and hsa‐miR‐202 exhibiting lessened expression after pemetrexed exposure . In breast cancer miR‐9 more directly targets and inhibits MTHFD2 to suppress the proliferation of breast cancer cells .…”

Section: Discussionmentioning

confidence: 99%

MicroRNA‐33a‐5p suppresses colorectal cancer cell growth by inhibiting MTHFD2

Yan

Zhang

Lei

et al. 2019

Clin Exp Pharma Physio

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Colorectal cancer (CRC) is one of the most common malignancies with high levels of invasiveness, drug resistance and mortality, but the internal mechanisms of CRC are largely unknown. MicroRNAs (miRs) have been reported to be involved in the development of CRC, and numerous studies have demonstrated that the abnormal expression of miR‐33a‐5p might be associated with CRC. However, the function and downstream mechanism of miR‐33a‐5p in colorectal cancer (CRC) remains unclear. Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), a mitochondrial enzyme involved in folic acid metabolism, interestingly was confirmed to be one of the target genes of miR‐33a‐5p in the present study. We first confirmed that miR‐33a‐5p in CRC tissues and cell lines were downregulated (P < 0.05), and that the proliferation, clone formation capacities, G1/S progression, and migration capacities of the two CRC cell lines HCT116 cells and HT29 were suppressed by miR‐33a‐5p overexpression in vitro (P < 0.05). Ctrl HCT116 and miR‐33a‐5p‐overexpressing HCT116 were injected into nude mice. In vivo tumour formation was significantly suppressed by miR‐33a‐5p overexpression (P < 0.05) as well as the proliferation marker Ki67 (P < 0.05). Additionally, MTHFD2 protein expression was significantly enhanced in CRC tissues. From bioinformatics predictions and a luciferase report analysis, MTHFD2 was confirmed to be one of the target genes of miR‐33a‐5p. In contrast to the role of miR‐33a‐5p overexpression, MTHFD2 overexpression promoted the proliferation and migration of HCT116 and HT29 cells (P < 0.05), which confirmed that MTHFD2 was a functional target gene of miR‐33a‐5p. In conclusion, miR‐33a‐5p inhibits the growth and migration of CRC by targeting MTHFD2.

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Gene and MicroRNA Perturbations of Cellular Response to Pemetrexed Implicate Biological Networks and Enable Imputation of Response in Lung Adenocarcinoma

Cited by 14 publications

References 62 publications

Upregulated miRNA‑182‑5p expression in tumor tissue and peripheral blood samples from patients with non‑small cell lung cancer is associated with downregulated Caspase 2 expression

Upregulated miRNA‑182‑5p expression in tumor tissue and peripheral blood samples from patients with non‑small cell lung cancer is associated with downregulated Caspase 2 expression

Expression levels and co‑targets of miRNA‑126‑3p and miRNA‑126‑5p in lung adenocarcinoma tissues: Αn exploration with RT‑qPCR, microarray and bioinformatic analyses

MicroRNA‐33a‐5p suppresses colorectal cancer cell growth by inhibiting MTHFD2

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